DOI: 10.1111/jdv.

12479 JEADV

ORIGINAL ARTICLE

A randomized, investigator-blinded efficacy assessment

study of stand-alone emollient use in mild to moderately
severe atopic dermatitis flares
I. Angelova-Fischer,1,* G. Neufang,2 K. Jung,2 T.W. Fischer,1 D. Zillikens1
1
€beck, Lu
Department of Dermatology, University of Lu €beck, Germany
2
Beiersdorf AG, Hamburg, Germany
*Correspondence: I. Angelova-Fischer. E-mail: irena.angelova-fischer@uk-sh.de

Abstract
Background Whereas emollients are integral to the long-term management of atopic dermatitis (AD), the evidence for
their efficacy in disease flares is limited.
Objective We aimed to investigate the stand-alone efficacy of an emollient formulation with regard to improvement of
the clinical symptoms, skin barrier function and reduction of pathogenic bacterial colonization in acute stage of AD.
Materials and methods Twenty AD volunteers aged 12–65 years with symmetric, mild to moderately severe inflam-
matory lesions on the forearms/arms were recruited for the study. At inclusion, the forearms/arms of each volunteer were
randomized to receive for 1 week either an o/w formulation containing licochalcone A (Glycyrrhiza Inflata root extract),
decanediol, menthoxypropanediol and x-6-fatty acids (emollient arm) or 1% hydrocortisone (HC arm); after 1 week, the
application of the emollient and HC were discontinued and the volunteers applied a w/o emollient containing licochal-
cone A and x-6-fatty acids on both arms for further 3 weeks. The outcomes included reduction of the clinical and itch
severity, decrease in S.aureus colonization, improvement of the barrier function, skin hydration and skin tolerability
assessed after 1 week (D7) and after 4 weeks (D28) respectively.
Results In both arms, there was a significant decrease in the severity score, itch intensity, erythema and TEWL on D7
and D28 compared to baseline. In addition, emollient use resulted in pronounced decrease in S.aureus colonization and
significant increase of skin hydration on D7. The comparison of the outcomes, based on percentage change from base-
line, showed no significant differences between the emollient and HC arm at any time point.
Conclusions The results of the study indicate that the 1-week stand-alone application of an emollient, tailored to tar-
get inflammation, pruritus, compromised barrier function and pathogenic bacterial colonization may offer benefit for the
improvement of mild to moderately severe localized flares of AD.
Received: 10 January 2014; Accepted: 19 February 2014

Conflict of interest
I. Angelova-Fischer has been investigator for and received honoraria as a speaker from Beiersdorf AG.

Funding Source
The study was funded by Beiersdorf AG.

Introduction along with restoration of the skin barrier homeostasis and

Atopic dermatitis (AD) is a chronic, relapsing and intensely pru-
ritic inflammatory skin disease in result of a complex interplay
of genetic, immunologic and environmental factors.1–3 The dis-
ease occurs most frequently in infancy or early childhood and
may persist throughout life in up to 40–60% of the cases. AD
causes substantial physical and psychological discomfort for the
patients and the affected families and may have considerable
negative impact on life quality.4
The management of AD requires efficient control of the
flares by treatment of the acute inflammatory symptoms
avoidance of the relevant triggering or disease-aggravating
factors.5 Topical steroids and immunomodulators are first-
line treatment of the disease flares, whereas the long-term
management is based on the use of emollients that aim to
improve skin hydration, maintain the barrier integrity,
relieve pruritus and prevent new flares.6–8 Although inde-
pendent lines of research suggest that the use of emollients
may result in enhanced therapeutic responses and improved
outcomes, so far there has been limited evidenced-based
proof concerning the stand-alone efficacy of emollients in

© 2014 The Authors

JEADV 2014, 28 (Suppl. 3), 9–15 Journal of the European Academy of Dermatology and Venereology © 2014 European Academy of Dermatology and Venereology
10
acute stage of disease.5,6,9 Therefore, in the present study,
we investigated the effects of an o/w formulation containing
licochalcone A (Glycyrrhiza Inflata root extract), decanediol
(decylene glycol), menthoxypropanediol and x-6-fatty acids
with regard to reduction of the lesional severity, pruritus
relief, improvement of the skin barrier function and reduc-
tion in pathogenic bacterial colonization in AD patients with
mild to moderately severe disease flare.
Materials and methods
Study population
Twenty volunteers with mild to moderately severe AD aged 12–
65 years (16 female and 4 male; median age 26.2 years), meeting
the UK Working Party Criteria were enrolled in the study.10 The
inclusion criteria were defined as follows: (1) Presence of at least
two inflammatory lesions of comparable clinical severity sym-
metrically on the forearms/arms; and (2) SCORAD intensity
parameters (local SCORAD) in the test area greater than 4 and
no greater than 8. Volunteers with SCORAD intensity parame-
ters in the test area lesser than 4 and greater than 8 or with severe
forms of AD as well as history for other skin or systemic diseases
were not considered eligible for participation. The exclusion
criteria were further defined as follows: (1) Treatment with
topical or systemic corticosteroids, immunosuppressive agents,
UV-light as well as topical or systemic antimicrobial agents in
the last 2 weeks preceding the study; (2) Previously known or
suspected delayed-type sensitization; (3) Pregnancy or lactation
and (4) Participation in another study within the preceding
4 weeks.
The protocol was approved by the Ethics Committee of the
University of L€ ubeck (Nr. 08-228). The study was performed
according to the principles of the Declaration of Helsinki and
all participants gave written informed consent/assent before-
hand.
Study design
The study was a 4-week, prospective, randomized, investigator-
blinded, controlled half-side comparison test. On recruitment,
the forearms/arms of each volunteer were randomized to receive
Screening Baseline +1 week
AC or 1%HC
Day-5/Day-1 Day 0 (D0) Day 7 (D7)
Evaluation Evaluation
Initiation Discontinuation
AC or 1%HC use AC and 1%HC use
Figure 1 Study flow chart.
JEADV 2014, 28 (Suppl. 3), 9–15 Journal of the European Academy of Dermatology and Venereology © 2014 European Academy of Dermatology and Venereology
Angelova-Fischer et al.
within the first week either an o/w formulation containing lic-
ochalcone A, decanediol, menthoxypropanediol and x-6-fatty
acids (AC formulation; study arm, respectively, further referred
to as AC-AL or emollient arm) or 1% hydrocortisone (HC;
study arm further referred to as HC-AL or hydrocortisone arm).
After 1 week, the application of the AC formulation and HC
were discontinued and the volunteers were asked to apply a w/o
emollient containing licochalcone A and x-6-fatty acids
(referred to as AL) on both forearms/arms twice daily for further
3 weeks (Fig. 1). Monitoring of the outcome parameters was
performed at baseline (D0), after 1 week (D7) and after 4 weeks
(D28).
Outcomes and methods of assessment
The outcomes included reduction of the lesional severity and
itch intensity, improvement of the skin barrier function, assessed
by the changes in transepidermal water loss (TEWL) and stra-
tum corneum hydration (capacitance), reduction in the lesional
skin colonization with S.aureus and skin tolerability.
Clinical severity scoring and itch severity assessment
The clinical severity scoring was performed by assessment of the
SCORAD intensity parameters in the test area (local SCORAD)
taking into consideration the presence of erythema, exsudation,
papulation, excoriations, lichenification and skin dryness on a
0–3 scale as previously described.11
The itch intensity was assessed by the volunteers using a visual
analogue scale from 0 (no perceptible itch in the test area) to 10
(worst imaginable itch).
Assessment of erythema and skin barrier function
The non-invasive assessment of erythema, TEWL and skin
hydration was performed on the volar surface of the forearms/
arms. Erythema was measured with the skin Colorimeter CL400
and expressed in the L*a*b* system. TEWL was measured with
the open chamber system (Tewameter TM300) and skin hydra-
tion was assessed by measuring capacitance (Corneometer
CM825), all devices from Courage and Khazaka Electronics
(Cologne, Germany). The assessment of erythema and TEWL
was based on the average value of three consecutive measure-
+4 weeks
AL
Day 28 (D28)
Evaluation
Discontinuation
AL use/Study end/
© 2014 The Authors
Stand-alone emollient therapy in AD 11

ments per field performed by the same observer; the assessment
of skin hydration was based on the average value of five consecu-
tive measurements per field. All measurements were performed
under controlled environmental conditions (room temperature
20  2°C; average relative humidity 40–45%) and according to
the published guidelines.12–16
Table 1 Clinical and non-invasive bioengineering assessment at
baseline (D0), after 1 week (D7) and after 4 weeks (D28): (a)
SCORAD intensity parameters (local SCORAD) and itch severity in
the test area (median and interquartile range); (b) Lesional skin
erythema (a*-value), transepidermal water loss (TEWL) and
capacitance (mean  SEM; n = 18).
(a)

D0 D7 D28
Quantification of lesional skin S.aureus colonization
density Local SCORAD
The assessment of lesional skin S.aureus colonization was per- AC-AL 7.0 (5.0–8.0) 3.5 (1.5–6.5)** 4.0 (2.0–6.5)**
HC-AL 6.5 (4.0–8.0) 3.0 (2.0–4.5)*** 4.25 (2.5–6.0)**
formed according to a previously validated and published proto-
Itch severity (VAS 0–10)
col.17 The samples were collected by gently rubbing the skin with
AC-AL 3.5 (2.0–5.75) 1.75 (0.0–4.0)** 1.75 (0.0–3.5)**
1 mL eluant buffer solution for 1 min with the help of a teflon HC-AL 3.75 (2.25–5.25) 1.0 (0.0–2.0)*** 1.5 (0.0–3.5)*
ring and spatula. After transferring the sample into 2 mL sterile
(b)
Eppendorf tubes (Eppendorf, Hamburg, Germany), 100 lL of
the original suspension as well as 1:10 and 1:100 dilutions of the D0 D7 D28
same were plated in duplicate on RAPID-Staph agar (Bio-Rad, a*-value/AU/
Munich, Germany) and the colonies were counted after 48-h AC-AL 16.47  0.71 14.73  0.66* 14.52  0.64**
cultivation at 37°C and 5% CO2. HC-AL 16.28  0.75 13.71  0.51** 14.38  0.64*
TEWL/g/m2/h/
Statistical analysis AC-AL 31.32  3.54 21.40  3.09* 20.45  2.52**
Statistical analysis was performed using GraphPrism Version HC-AL 26.63  2.70 14.20  0.85*** 21.24  3.06*
Capacitance/AU/
4 (GraphPad Software Inc, San Diego, CA, USA). A P-value
AC-AL 20.86  2.53 29.10  3.97* 27.44  3.40
<0.05 was considered statistically significant. The changes in
HC-AL 22.40  2.45 24.56  3.38 28.38  3.94
the severity score, pruritus intensity, erythema (a*-value),
TEWL, capacitance and S.aureus counts for each study arm *P < 0.05, **P < 0.01, ***P < 0.001. Level of significance <0.05, com-
over time were analysed by repeated measures ANOVA or pared to baseline. AC-AL-emollient arm; HC-AL-hydrocortisone arm;
Friedmann test for the respective parameter; for P-values less VAS-visual analogue scale; AU-arbitrary units.
than 0.05 a post hoc test was performed. The differences
between the study arms at baseline, after 1 week and after
4 weeks were analysed by unpaired t-test or Mann–Whitney improvement of the skin condition in the test area (Fig. 2); on
test. In the respective tables and figures, the values are D7 the local SCORAD was significantly reduced compared to
expressed as mean and standard error (SEM), except for the baseline (for arm AC-AL and HC-AL, respectively, P < 0.01 and
clinical severity score and itch intensity, expressed as median P < 0.001). At the end of the study (D28), the severity score was
and interquartile range. still significantly decreased compared to baseline in both arms
(P < 0.01 for both, arm AC-AL and HC-AL). The reduction in
Results the local SCORAD on D7 was 37.39% and 45.5% from base-
Eighteen volunteers (14 female and 4 male, median age line for, respectively, the emollient and HC arm; on D28, respec-
26.5 years; median total SCORAD at inclusion 31.0) completed tively, 31.74% and 31.98% (Fig. 3a). The differences
the study per protocol. Two volunteers were excluded from fur- between the study arms with regard to percentage change were
ther participation within, respectively, the second and fourth not significant.
study week because of worsening of the skin condition outside The assessment of itch intensity showed significant reduction
the test area that required topical treatment. in the visual analogue scale values for both study arms on D7
and D28 compared to baseline (Table 1a); on D28 there was no
Significant reduction of the clinical severity score and itch significant difference with regard to the outcome between the
intensity in result of stand-alone emollient use emollient and HC arm (Fig. 3b).
The clinical severity score and itch intensity assessment at
baseline (D0), after 1 week (D7) and after 4 weeks (D28) are Significant decrease of erythema and TEWL as well as
presented in Table 1a. increase of skin hydration following stand-alone emollient
At the beginning of the study, there were no significant differ- application
ences in the severity score between the study arms. The applica- The results from the non-invasive measurements of erythema
tion of AC and HC within the first study week resulted in (a*-value), TEWL and capacitance on D0, D7 and D28 are

© 2014 The Authors

JEADV 2014, 28 (Suppl. 3), 9–15 Journal of the European Academy of Dermatology and Venereology © 2014 European Academy of Dermatology and Venereology
12 Angelova-Fischer et al.

D0 AC-AL HC-AL D7 AC-AL HC-AL D28 AC-AL HC-AL

Figure 2 Clinical photographs of the test area at baseline (D0), after 1 week (D7) and after 4 weeks (D28): AC-AL-emollient arm; HC-AL-
hydrocortisone arm.

Local SCORAD (a)

(a) AC-AL HC-AL

100
% change of baseline

80
Local SCORAD

60

40

20

0
D0 D7 D28

Itch severity assessment (b) TEWL: Percentage change from baseline

(b) AC-AL HC-AL AC-AL HC-AL
120

100 100
% from baseline

80 80
% from baseline
VAS

60
60
TEWL

40
20
0
D0 D7
Figure 3 Comparison of the outcomes, assessed as percentage
change from baseline: (a) Clinical severity in the test area (local
SCORAD); (b) Itch intensity. Mean  SEM, normalized data
(n = 18); AC-AL-emollient arm, HC-AL-hydrocortisone arm, VAS-
visual analogue scale.
presented in Table 1b. At baseline, there were no significant
differences in the measured parameters between the study
arms.
The mean a*-values at the beginning of the study
were 16.47  0.71 and 16.28  0.75 AU for, respectively, arm
AC-AL and HC-AL. On D7 and D28, the a*-values were
significantly reduced compared to baseline for both study arms
(AC-AL:14.73  0.66 and 14.52  0.64 AU, respectively,
P < 0.05 and P < 0.01 compared to D0; HC-AL: 13.71  0.51
and 14.38  0.64 AU, respectively, P < 0.01 and P < 0.05). The
40
20
D28
0
D0 D7 D28
Figure 4 (a) Significant reduction in transepidermal water loss
(TEWL) in the emollient as well as hydrocortisone arm after 1 week
(D7) and after 4 weeks (D28) compared to baseline (D0). (b) Com-
parison of the outcomes, assessed as percentage change of base-
line. Mean  SEM (n = 18); level of significance <0.05, *P < 0.05,
**P < 0.01, ***P < 0.001. AC-o/w formulation containing licochal-
cone A (Glycyrrhiza Inflata root extract), decanediol, menthoxypro-
panediol and x-6-fatty acids, HC-1% hydrocortisone, AL-w/o
formulation containing licochalcone A and x-6-fatty acids.
differences between the study arms assessed as percentage change
from baseline on D7 and D28 were not significant (data not
shown).
For both study arms, on D7 there was significant decrease in
TEWL compared to baseline (AC-AL: on D0 and D7,
31.32  3.54 and 21.40  3.09 g/m2/h, P < 0.05; HC-AL,

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JEADV 2014, 28 (Suppl. 3), 9–15 Journal of the European Academy of Dermatology and Venereology © 2014 European Academy of Dermatology and Venereology
Stand-alone emollient therapy in AD 13

Skin hydration Table 2 Skin tolerability assessment: Percentage (number) of vol-

40 * unteers reporting the respective symptom using a standardized
questionnaire. AC-o/w formulation containing licochalcone A
(Glycyrrhiza Inflata root extract), decanediol, menthoxypropanediol
Capacitance (AU)

30
and x-6-fatty acids, HC-1% hydrocortisone, AL- w/o formulation
containing licochalcone A and x-6-fatty acids; conform with the
20 application, the data for AC and HC refer to D7 and for AL to D28
(n = 18)
10 Symptom AC HC AL
Erythema 5.6% (1/18) 5.6% (1/18) 0.0% (0/18)
0 Scaling 0.0% (0/18) 5.6% (1/18) 0.0% (0/18)
D0 D7 D28 D0 D7 D28
Skin dryness 5.6% (1/18) 5.6% (1/18) 0.0% (0/18)
AC AL HC AL
Burning 11.1% (2/18) 16.7% (3/18) 5.6% (1/18)
Stinging 0.0% (0/18) 0.0% (0/18) 0.0% (0/18)
Figure 5 Skin hydration: significant increase in capacitance in the
emollient arm on D7 compared to D0. Mean  SEM (n = 18); level Skin tightness 5.6% (1/18) 5.6% (1/18) 0.0% (0/18)
of significance <0.05, *P < 0.05. AC-o/w formulation containing Itch 22.2% (4/18) 11.1% (2/18) 5.6% (1/18)
licochalcone A (Glycyrrhiza Inflata root extract), decanediol, menth- Other 0.0% (0/18) 0.0% (0/18) 5.6% (1/18)
oxypropanediol and x-6-fatty acids, HC-1% hydrocortisone, AL-
w/o formulation containing licochalcone A and x-6-fatty acids,
AU-arbitrary units.
Reduced colonization of the skin lesions with S.aureus
The quantitative analysis of lesional skin S.aureus colonization
throughout the study showed pronounced and consistent reduc-
S.aureus (CFU/ml)
tion in the bacterial counts on the emollient (AC-AL) arm
AC-AL HC-AL
400 000 (Fig. 6).

300 000
Skin tolerability and amount of used steroid
200 000
The skin tolerability assessment data based on the reported sub-
jective symptoms throughout the study are presented in Table 2.
100 000 The average amount of used HC within the first study week was
6.03 g per volunteer.
0
D0 D7 D28

Figure 6 Lesional skin S.aureus colonization density at baseline
(D0), after 1 week (D7) and after 4 weeks (D28). Mean  SEM;
level of significance <0.05. AC-AL-emollient arm, HC-AL-hydrocor-
tisone arm.
respectively, 26.63  2.70 and 14.20  0.85 g/m2/h,
P < 0.001). On D28, the mean TEWL values for both arms were
still significantly reduced compared to D0 (D28: arm AC-AL
and HC-AL, 20.45  2.52 and 21.24  3.06 g/m2/h, respec-
tively, P < 0.01 and P < 0.05 compared to D0; Fig. 4a). The
comparison of TEWL assessed as percentage change from base-
line throughout the study showed no significant differences
between the study arms (Fig. 4b).
The changes in skin hydration (capacitance) are shown in
Fig. 5. The application of the emollient within the first study
week resulted in significant increase in capacitance on D7
compared to baseline (D0 and D7, respectively, 20.86  2.53
and 29.10  3.97 AU, P < 0.05), whereas the changes in the HC
arm were not significant (D0: 22.40  2.45 AU, D7:
24.56  3.38 AU; P > 0.05).
Discussion
In the present study, we have shown that the stand-alone appli-
cation of an emollient, tailored to target inflammation, pruritus,
compromised barrier function and pathogenic bacterial coloni-
zation is an efficient and safe approach for improvement of mild
to moderately severe AD flares. As 1% HC, the 1-week twice
daily application of AC lead to significant reduction in the sever-
ity of signs and symptoms, improvement of the skin barrier
function and decrease in lesional skin S.aureus colonization den-
sity. There were no significant differences with respect to the
time frame and the scale of exerted effects between the study
arms; in addition to the efficacy of AC, the findings for compa-
rable outcomes between the emollient (AC-AL) and hydrocorti-
sone (HC-AL) arm at the end of the study suggest the steroid-
sparing potential of the emollient regimen.
The efficacy of licochalcone A for improvement of the clinical
manifestations of AD has been initially suggested by the findings
of a controlled, randomized, investigator-blinded study in
children with mild to moderately severe disease that showed
significant reduction in SCORAD and lack of significant differ-
ences in the outcomes after 6-week twice daily application of a
licochalcone A-based emollient compared to 1% HC.18

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14
Licochalcone A is a reversely constructed chalcone specific
for the Xynjiang licorice root Glycyrrhiza inflata, used in cos-
metic formulations due to its potent anti-inflammatory and
antioxidative properties.19–21 Experimental studies have shown
that licochalcone A-rich extracts from G. inflata and synthetic
licochalcone A suppress the production of pro-inflammatory
mediators and cytokines such as PGE2, LTB4, IL-6 and TNF-a
in in vitro systems relevant to the skin such as dermal fibro-
blasts, granulocytes, dendritic cells and human skin equiva-
lents.22–24 The in vitro findings have been further confirmed
by in vivo studies showing the efficacy of licochalcone A-con-
taining formulations for reducing experimentally induced ery-
thema, improvement of the inflammatory signs in patients
with rosacea and recently – in mild to moderately severe
inflammatory forms of acne.24–26 The findings of the present
study extend these observations and provide new evidence for
the anti-inflammatory effects of licochalcone A in mild to
moderately severe AD, on the basis of clinical assessment and
non-invasive skin bioengineering methods.
Pruritus is a major diagnostic criterion and a cardinal
symptom of AD.10,27,28 Though the first-line anti-inflamma-
tory agents such as topical steroids and calcineurin inhibitors
are known to induce short-term improvement, the achieve-
ment of lasting relief is a challenge and a most important goal
in disease management.29,30 The pathogenesis of itch related
to AD involves numerous factors within the skin, nervous sys-
tem and the environment and recent advances indicate a criti-
cal role for different thermosensitive members of the transient
receptor potential (TRP) ion channels superfamily in the
transmission and modulation of itch.31–34 Independent lines of
research provide evidence that both the generation and the
alleviation of itch is temperature-dependent. Skin cooling and
topical application of substances that induce a cooling sensa-
tion upon contact with the skin and mucosae such as men-
thol, eucalyptol or icilin have been shown to mitigate
experimentally induced and disease-related itch.34–37 The cool-
ing sensation has been further shown to be mediated by the
activation of TRPM8, a thermosensitive calcium-permeable
channel expressed in the sensory neurons and activated by
temperatures ≤28°C as well as cooling agents suggesting that
TRPM8 may be a novel pharmacological target for the man-
agement of itch.32,34,38–41 The findings of the study are consis-
tent with this concept and provide initial in vivo evidence for
pruritus relief in result of the use of an emollient containing
methoxypropanediol, a TRPM8 agonist, in atopic skin.
A strong line of publications shows the positive correlation
between S.aureus colonization density and AD severity.42–44 Ato-
pic skin provides a favourable environment for increased S.aur-
eus adherence and proliferation attributed to distinct,
interrelated pathomechanisms including compromised barrier
integrity, altered sphingolipid metabolism45–49 and expression of
antimicrobial peptides,50 upregulation of extracellular matrix
JEADV 2014, 28 (Suppl. 3), 9–15 Journal of the European Academy of Dermatology and Venereology © 2014 European Academy of Dermatology and Venereology
Angelova-Fischer et al.
adhesins51,52 as well as enhanced pathogen binding to areas of
Th2-mediated inflammation.44,53 Earlier publications indicate
that 30–60% of the S.aureus strains isolated from AD patients
produce exotoxins with superantigen properties that exert
potent disease-promoting effects while at the same time, con-
tribute to induction of corticosteroid resistance and alter the
therapeutic responses.54–57
In view of the relevance of S.aureus colonization for disease
exacerbation and chronicity, the reduction in the bacterial den-
sity in result of emollient use is an important finding of our
study. In addition to direct S.aureus targeting by decanediol, the
active antimicrobial component of the AC formulation, the
observed effects may have been further enhanced by the
improvement of the compromised barrier conditions through
reduction in the lesional severity, decrease in TEWL and increase
in skin hydration.58
In the present investigation, HC was used as a reference
for the effects exerted by the o/w formulation with respect to
clinical outcomes, barrier function and pathogenic bacterial
colonization. Independently of the study design, the formula-
tion is in a strict sense an emollient and therefore, not meant
as alternative to first-line topical medications intended to
treat AD. The presented results, however, provide proof-of-
principle that the stand-alone use of emollients may offer
benefit from a clinical, laboratory and patient’s perspective
and exert a steroid-sparing effect that would equal the
amount of used HC.
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